Dimeric piperidine, tetrahydropyridine and piperazine derivatives

ABSTRACT

The subject invention describes Novel dimer 4-phenylpiperidine, 4-phenyl-1,2,3,6-tetrahydropyridine, or 4-phenylpiperazine compounds or dimeric spirocyclic piperidine compounds having the general Formula I: ##STR1## wherein n is 1-5; 
     R 1  to R 4  are independently selected from hydrogen, halogen, C 1-6  alkyl, C 1-6  alkoxy, hydroxy, C 1-6  alkylthio, C 1-6  alkylsulfonyl, C 1-6  alkyl- or di-(C 1-6  alkyl)amino, cyano, trifluoromethyl, nitro, trifluoromethylthio or trifluoromethylsulfonyloxy; R 5  and R 6  are independently hydrogen, or C 1-6  alkyl; 
     X is O, S, SO, SO 2 , CO or (CH 2 ) m , m being 0 or 1, or X is NR 7 , R 7  being H, C 1-6  alkyl, cycloalkyl, cycloalkylalkyl, phenyl, or phenylalkyl, or X is CR 8  R 9 , wherein R 8  and R 9  are independently selected from the group consisting of hydroxy and the substituents defined under R 7 , any phenyl group being optionally substituted with one or more substituents selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, hydroxy, C 1-6  alkylthio, C 1-6  alkylsulfonyl, C 1-6  alkyl or di(C 1-6  alkyl)amino, cyano, trifluoromethyl or trifluoromethylthio; and 
     Z 1  is O, S, (CH 2 ) q , q being 1,2 or 3, or Z 1  is CH 2  O, CH 2  S, CH 2  CH 2  O, CH 2  CH 2  S, CH═CH, CH═CHCH 2 , CH 2  OCH 2  CH 2  SCH 2 , CH═CH--O, or CH═CH--S; and 
     Z 2  is O, S or (CH 2 ) p , p being 0 or 1, with the proviso that Z 1  may not be O, S or (CH 2 ) q , wherein q is 1 when Z 2  is (CH 2 ) p  wherein p is 0; 
     or an acid addition salt thereof. These compounds are potent sigma receptor ligands thus being useful for the treatment of anxiety, psychosis, epilepsy, convulsion, movement disorders, motor disturbances, amnesia, cerebrovascular diseases senile dementia of the Alzheimer type or Parkinson&#39;s disease.

This is a continuation of international application Ser. No.PCT/DK93/00198, filed Jun. 9, 1993.

This is a continuation of international application Ser. No.PCT/DK93/00198, filed Jun. 9, 1993 published as WO93/25527, Dec. 23,1993.

The present invention relates to a novel class of dimeric piperidine,1,2,3,6-tetrahydropyridine and piperazine derivatives in which thenitrogen atoms of the six-membered basic rings are linked together via aspacer chain to form a symmetrical dimeric bis(1-piperidyl),bis(1,2,3,6-tetrahydro-1-pyridyl), or bis(1-piperazinyl) compound. Thesedimers potently bind to sigma receptors and are therefore useful in thetreatment of certain psychic and neurologic disorders. The piperidines,1,2,3,6-tetrahydropyridines, or piperazines are substituted with4-phenyl groups or the piperidine derivatives might be spiro-joined inthe 4-position to a hetero- or carbocyclic ring system.

Various 4-phenylpiperidine, 4-phenyl-1,2,3,6-tetrahydropyridines,4-phenylpiperazines, and spirocyclic piperidine derivatives havepreviously been described:

International Patent Application No WO 91/09594 generically describes abroad class of sigma receptor ligands some of which are4-phenylpiperidine, -tetrahydropyridine or -piperazine compounds havingan optionally substituted "aryl"- or "heteroaryl" -alkyl, -alkenyl,-alkynyl, -alkoxy or -alkoxyalkyl substituent on the ring N-atom. Theterms "aryl" and "heteroaryl" are defined by mention of a number of suchsubstituents.

European patent publication No EP 0 414 289 A1 generically discloses aclass of 1,2,3,4-tetrahydro-spiro[naphthalene-1,4'-piperidine] and1,4-dihydro-spiro[naphthalene-1,4'-piperidine] derivatives substitutedat the piperidine N-atom with a "hydrocarbon" group alleged to haveselective sigma receptor antagonistic activity. The term "hydrocarbon"as defined in said patent covers all possible straight chained, cyclic,heterocyclic, etc. groups. However, only compounds having benzyl,phenethyl, cycloalkylmethyl, furyl- or thienylmethyl or lower alkyl oralkenyl as the "hydrocarbon" substituent at the piperidine nitrogen atomare specifically disclosed. The compounds are stated to displacetritiated di-tolyl guanidine (DTG) from sigma sites with potenciesbetter than 200 nM. As a particularly preferred compound is mentioned1'-benzyl-1,2,3,4-tetrahydro-spiro[naphthalene-1,4'-piperidine].

European patent publication No EP 0 445 974 A2 generically describes thecorresponding spiro[indane-1,4'-piperidine] andspiro[benzocycloheptene-5,4'-piperidine] derivatives. Again thecompounds are only stated to displace tritiated ditolyl guanidine (DTG)from sigma sites with potencies better than 200 nM.

EP Application No. EP-A2-0 431 943 relates to a further extremely broadclass of spiropiperidine compounds substituted at the piperidine N-atomand claimed to be useful as antiarrhythmics and for impaired cardiacpump function. The said application exemplifies several compounds, themajority of which contain an oxo and/or a sulfonylamino substituent inthe spiro cyclic ring system. Of the remainder compounds, the main parthas another polar substituent attached to the spiro nucleus and/or theyhave some polar substituents in the substituent on the piperidineN-atom. No suggestion or indication of effect of the compounds on thesigma receptors is given.

From studies of the biology and function of sigma receptors, evidencehas been presented that sigma receptor ligands may be useful in thetreatment of psychosis and movement disorders, such as dystonia andtardive dyskinesia, and motor disturbances associated with Huntington'schorea or Tourette's syndrome and in Parkinson's disease (Walker, J. M.et al, Pharmacological Reviews, 1990, 42, 355). It has been reportedthat the known sigma receptor ligand rimcazole clinically shows effectsin the treatment of psychosis (Snyder, S. H., Largent, B. L. J.Neuropsychiatry 1989, 1, 7) and that a group of sigma receptor ligandsshow antihallucinogenic activity in animal models (international PatentPublication No WO 9103243).

Furthermore, some sigma receptor ligands have been found to be involvedin modulation of NMDA receptor mediated events in the brain and to actas anti-ischemic agents in in vivo tests (Rao, T. S. et al, MolecularPharmacology, 1990, 37, 978 and Rao, T. S. et al, Life Sciences, 1990,47, PL1-PL5). In addition to ischemia they may also be useful in thetreatment of other such events, e.g. epilepsy and convulsion.

Also, some sigma receptor ligands have been found to show anti-amnesiceffects in an animal model (Early et al., Brain Research 1991, 546,281-286).

Sigma ligands have been shown to influence central acetylcholine levelsin animal models (Matsuno et al, Brain Research 1992, 575, 315-319;Junien et al, Eur. J. Pharm. 1991, 200, 343-345) and may, therefore,have potential in the treatment of senile dementia, e.g. of theAlzheimer type.

Finally some guanidine derivatives having sigma receptor activity havebeen disclosed to be useful as anxiolytics (International PatentPublication No. WO 9014067).

Accordingly, agents potently acting on the sigma receptors in thecentral nervous system may be useful in the therapy of such conditions.

It has now been found that the novel class of dimeric piperidine,1,2,3,6-tetrahydropyridine and piperazine compounds are potent sigmareceptor ligands.

Accordingly the present invention provides the novel dimeric4-phenylpiperidine, 4-phenyl-1,2,3,6-tetrahydropyridines, or4-phenylpiperazine derivatives or dimeric spirocyclic piperidinecompounds having the general Formula I: ##STR2## wherein n is 1-5;

R¹ to R⁴ are independently selected from hydrogen, halogen, lower alkyl,lower alkoxy, hydroxy, lower alkythio, lower alkylsulfonyl, lower alkyl-or dialkylamino, cyano, trifluoromethyl, nitro, trifluoromethylthio ortrifluoromethylsulfonyloxy;

R⁵ and R⁶ are independently hydrogen, lower alkyl or they may be linkedtogether thereby forming an ethylene or propylene bridge;

X is O, S, SO, SO₂, CO or (CH₂)_(m), m being 0 or 1, X is NR⁷, R⁷ beingH, lower alkyl, cycloalkyl, cycloalkylalkyl, phenyl, or phenylalkyl, orX is CR⁸ R⁹, wherein R⁸ and R⁹ are independently selected from the groupconsisting of hydroxy and the substituents defined under R⁷, any phenylgroup being optionally substituted; and

I) Z¹ is defined as R¹ to R⁴ and Z² is (CH₂)_(p) wherein p is 0; and Yis N, CH or C; and the dotted line indicates an optional bond, i.e.represents a bond when Y is C; or

II) Z¹ and Y are linked together via a single bond, thereby forming aspirocyclic junction; in which case

Y is C and the dotted line represent no bond; and

Z¹ is O, S, (CH₂)_(q), q being 1,2, or 3, or Z¹ is CH₂ O, CH₂ S, CH₂ CH₂O, CH₂ CH₂ S, CH═CH, CH═CHCH₂, CH₂ OCH₂, CH₂ SCH₂, CH═CH--O, orCH═CH--S; and

Z² is O, S, or (CH₂)_(p), p being 0 or 1, with the proviso that Z¹ maynot be O, S or (CH₂)_(q), wherein q is 1 when Z² is (CH₂)_(p) wherein pis 0;

or an acid addition salt or prodrug thereof.

Some of the compounds of general Formula I may exist as optical isomersthereof; and such optical isomers are also embraced by the invention.

In the definition of general Formula I, halogen means fluoro, chloro,bromo or iodo.

The terms lower alkyl, lower alkoxy, lower alkylthio and loweralkylsulphonyl, etc. designate such branched or unbranched groups havingfrom one to six carbon atoms inclusive. Exemplary of such groups aremethyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl,2-methyl-1-propyl, methoxy, ethoxy,1-propoxy, 2-propoxy, methylthio,ethylthio, 1-propylthio, 2-propylthio, methylsulphonyl, ethylsulphonyl,or the like. Similarly, lower alkyl- or dialkylamino designate suchgroups containing lower alkyl as defined above and lower alkenyl isintended to mean an alkenyl group (branched or unbranched) containingfrom two to six carbon atoms, for example ethenyl, 1-propenyl,2-propenyl, 3-propenyl, 2-buten-1-yl etc.

The term cycloalkyl designates a carbocycle having 3-8 carbon atomsinclusive.

The optional substituents in the phenyl groups may independently beselected from halogen, lower alkyl, lower alkoxy, hydroxy, loweralkylthio, lower alkylsulfonyl, lower alkyl- or dialkylamino, cyano,trifluoromethyl, or trifluoromethylthio. Each phenyl group may carry oneor more substituents.

In the definition of Z¹ under II) the groups listed may be oriented inboth directions, i.e. for example the group CH₂ O may be linked to the"Y"-group via either the C-atom or the O-atom.

The acid addition salts of the invention are pharmaceutically acceptablesalts of the compounds of Formula I formed with non-toxic acids.Exemplary of such organic salts are those with maleic, fumaric, benzoic,ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic,methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmitic, itaconic, glycolic,p-amino-benzoic, glutamic, benzene sulfonic and theophylline aceticacids, as well as the 8-halotheophyllines, for example8-bromo-theophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitricacids.

The compounds of the invention have been found to be potent sigmareceptor ligands displacing tritiated di-tolyl guanidine (DTG) fromsigma sites in vitro with high potencies, i.e. for many of the compoundswith IC₅₀ values below 1 nM. Furthermore, many of the present compoundshave proven to be very selective ligands for sigma receptors. Forexample with respect to α₁ adrenoceptors and dopamine D-2, serotonin5-HT_(1A) and 5-HT₂ receptors, ratios of binding IC₅₀ values(alpha/sigma, dopamine/sigma, 5-HT_(1A) /sigma, and 5-HT₂ /sigma,respectively) of 100->1000 have been found.

The compounds of the invention have the further advantage that the saltsthereof have a good water solubility. Furthermore, due to the fact thatthey are symmetrical dimers, some obvious advantages are obtained in themanufacture of the compounds.

Accordingly, the dimeric piperidine, 1,2,3,6-tetrahydropyridine, andpiperazine compounds of the present invention are useful in thetreatment of anxiety, psychosis, epilepsy, convulsion, movementdisorders, motor disturbances, amnesia, cerebrovascular diseases, seniledementia, e.g. of the Alzhemer type, and Parkinson's disease.

One preferred subgroup of the compounds of the invention comprises thecompounds of Formula I wherein Z¹ and Y are not linked together and Z²is (CH₂)_(p) where p=0, i.e.4-phenyl-piperidine,-1,2,3,6-tetrahydropyridine, and -piperazinecompounds.

Another preferred subgroup comprises compounds of Formula I wherein Z¹and Y are linked together thereby forming a spirocyclic ring system.

In Formula I the following are preferred definitions of the symbols:

n is 1, 2 or 3;

X is (CH₂)_(m), m being 0 or 1, X is NR⁷, R⁷ being lower alkyl,cycloalkyl or optionally substituted phenyl, or X is S, O or CR⁸ R⁹,wherein R⁸ is hydroxy or optionally substituted phenyl and R⁹ ishydrogen;

R² -R⁴ are independently selected from hydrogen, halogen, lower alkyland trifluoromethyl;

R⁵ and R⁶ are hydrogen

And if Z¹ and Y are linked together in order to form a spirocyclic ringsystem, Z¹ is (CH₂)_(q), q being 1, 2 or 3, CH₂ O, (CH₂)₂ O, CH═CH, O, Sor CH₂ S; and

Z² is (CH₂)_(p) wherein p is 0 or 1, or O.

Especially preferred spiropiperidine compounds of Formula I are thosewherein Z² is (CH₂)_(p), p being 0, Z¹ is (CH₂)_(q), q being 1, 2 or 3,CH₂ O, (CH₂)₂ O, CH═CH, O, S or CH₂ S, in particular CH₂ O, CH₂ S or(CH₂)₂ O.

Particularly preferred compounds are:

1,4-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]butane;

1,4-Bis[4-(4-fluorophenyl)piperidin-1-yl]butane;

1,4-Bis[4-(4-fluorophenyl)piperazin-1-yl]butane;

1,6-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]hexane;

1,4-Bis[6-fluoro-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]butane;

1,5-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]pentane;

1,4-Bis[spiro[isobenzothiophene-1(3H),4'-piperidin]-1'-yl]butane;

1,4-Bis[spiro[1-benzopyran-2,4'-piperidin]-1'-yl]butane;

1,4-Bis[spiro[1-benzopyran-4,4'-piperidin]-1'-yl]butane;

1,3-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]propane;

1,3-Bis[4-(4-fluorophenyl)piperidin-1-yl]propane;

1,2-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]ethane;

1,2-Bis[4-(4-fluorophenyl)piperidin-1-yl]ethane;

N,N-Bis[2-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-ylethyl]-N-cyclopentylamin;

1,4-Bis[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]butane;

N,N-Bis[2-[4-(4-fluorophenyl)piperidin-1-yl]ethyl]aniline;

1,5-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]-3-(4-fluorophenyl)pentane;

Bis[2-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-ylethyl]sulphide,difumarate;

In another aspect the present invention relates to a pharmaceuticalcomposition comprising at least one novel dimeric piperidine,1,2,3,6-tetrahydropyridine, or piperazine compounds having the abovedefined general Formula I or a pharmaceutically acceptable acid additionsalt or prodrug thereof in combination with one or more pharmaceuticallyacceptable carriers or diluents.

The pharmaceutical compositions of this invention may be administered byany suitable route, for example orally in the form of tablets, capsules,powders, syrups, etc., or parenterally in the form of solutions forinjection. For preparing such compositions methods well known in the artmay be used, and any pharmaceutically acceptable carriers, diluents,exipients, or other conventional additive in the art may be used.

Conveniently, the compounds of the invention are administered in unitdosage form containing said compound in an amount of about 0.01 to 50mg.

The total daily dose usually ranges from about 0.05 to 100 mg,preferably about 0.1-50 mg of the active compound of the invention.

In a further aspect the present invention relates to the use of dimericpiperidine, 1,2,3,6-tetrahydropyridine, and piperazine compounds havingthe above defined general Formula I or acid addition salts or prodrugsthereof for the manufacture of a pharmaceutical preparation for thetreatment of anxiety, psychosis, epilepsy, convulsion, movementdisorders, motor disturbances, amnesia, cerebrovascular diseases seniledementia of the Alzhemer type or Parkinson's disease.

The movement disorders and motor disturbances which may be treated bythe preparation according to the invention are e.g. dystonia and tardivedyskinesia and motor disturbances associated with Huntington's chorea orTourette's syndrome. Dystonia may be acute or tardive and may be causedby neuroleptics or have another reason.

Cerebrovascular diseases are such disorders caused by cerebralinfarction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoidhemorrhage, cerebral thrombosis, cerebral embolism, or the like, e.g,ischemia.

The compounds of Formula I may be prepared by

a) reducing the amide carbonyl groups of a compound of Formula II##STR3## wherein n' is 0-4, X, Y, R¹ -R⁶, Z¹, Z² and the dotted linesare as previously defined;

b) reducing the amide carbonyl group a of compound of Formula III##STR4## wherein n' is n-1, and n, X, Y, R¹ -R⁶, Z¹, Z² and the dottedlines are as previously defined;

c) alkylating a compound of formula IV ##STR5## wherein Y, R¹ -R⁶, Z¹,Z² and the dotted lines are as previously defined; with epichlorohydrinor an alkylating reagent of the formula V

    A--(CH.sub.2).sub.n --X--(CH.sub.2).sub.n --A              V

wherein X and n are as previously defined and A is a suitable leavinggroup such as halogen, mesylate or tosylate;

d) reductive alkylation of an amine of Formula IV with a dialdehyde ofthe Formula VI or a dicarboxylic acid of the formula VII

    OHC--(CH.sub.2).sub.n' --X--(CH.sub.2).sub.n' --CHO        VI

    HOOC--(CH.sub.2).sub.n' --X--(CH.sub.2).sub.n' --COOH      VII

wherein n' is 0 to 4, and X is as previously defined; or

e) reducing the double bonds in a compound of Formula I in order toobtain the corresponding saturated compound of Formula I. Such doublebonds are present when the dotted line represents a bond and/or when Z¹and Y are linked together in order to form a spiropiperidine compoundand Z¹ comprises a double bond whereupon the compound of Formula Iformed is isolated as the free base or a pharmaceutically acceptableacid addition salt thereof.

The reduction according to method a) may preferably be carried out in aninert organic solvent such as diethyl ether or tetrahydrofuran withreducing agents such as eg. lithium aluminium hydride, AlH₃ or diboraneat appropriate temperatures which are generally from room temperature toreflux temperature. Reductions of amides according to method b) areperformed similarly.

Alkylation of compounds of Formula IV according to method c) isconveniently performed in an inert organic solvent such as an alcohol ora ketone with a suitable boiling point, preferably in the presence of abase (potassium carbonate or triethyl amine) at reflux temperature.Epichlorohydrin is a particularly useful reagent for introducing apropylene chain substituted with hydroxy, i.e. for obtaining compoundsof Formula I wherein n is 1 and X is CHOH.

Reductive alkylation according to method d) is performed by standardliterature procedures. The aldehydes VI and carboxylic acids VII areeither commercially available or are prepared according to standardprocedures.

Reduction of double bonds according to method e) is generally performedby catalytic hydrogenation using Pd or Pt as catalysts in proticsolvents such as ethanol or methanol under acidic conditions.

The alkylating reagents V are either commercially available or may beprepared according to well known methods oxidizing either thecorresponding alcohols or reducing the carboxylic acids or appropriatederivatives thereof.

The diamides of Formula II are conveniently prepared by treating the1-unsubstituted derivatives IV with a suitable activated dicarboxylicacid derivative such as proper carboxylic acid chlorides or anhydridesaccording to known methods. The carboxylic acid derivatives are eithercommercially available or prepared according to standard procedures.Intermediate mono-amides III are similarly prepared by reaction of anω-halo substituted carboxylic acid via its activated form, such as theacid chloride or anhydride. The latter reaction might be performed in atwo step sequence: first reacting the activated acid part with one moleof compounds IV followed by reaction of the ω-halo part of the spacergroup with another mole of IV. These reactions are performed understandard acylation/alkylation conditions.

4-Phenylpiperidines of formula IV (Y═C and the dotted line indicating nobond) are either commercially available or prepared as described in eg.U.S. Pat. No. 2,891,066; McElvain et al. J. Amer. Chem. Soc. 1950, 72,3134; Bally et al Chem. Ber. 1887, 20. The corresponding4-phenyl-1,2,3,6-tetrahydropyridines of formula IV (Y═C and the dottedline indicating an extra bond) are prepared from N-protected4-piperidones by addition of properly substituted phenyl lithium orphenyl magnesium halides followed by acid catalyzed water elimination.The N-protecting group (carbamate, benzyl, sulphonyl, acetyl) is finallyremoved in a conventional manner. The3-phenyl-8-azabicyclo[3,2,1]oct-2-ene derivatives were preparedaccordingly from N-protected 8-azabicyclo[3,2,1]octan-3-ones.4-Phenylpiperidines are also conveniently prepared by catalytichydrogenation of the corresponding 4-phenyl-1,2,3,6-tetrahydropyridinesusing Pt as catalyst.

4-Phenylpiperazines of formula IV (Y═N and the dotted line indicating nobond) are either commercially available or prepared according to themethods in Martin et al. J. Med. Chem. 1989, 32, 1052-1056. Thesemethods include ringclosure reaction of properly substituted anilineswith bis-(2-chloroethyl)amine (eventually N-protected) by refluxing inhighboiling solvents as eg. chlorobenzene typically for some days (2-3),eventually followed by deprotection of an optional N-protection groupaccording to standard procedures.

The spiropiperidine derivatives of Formula IV wherein Z¹ and Y arelinked together and Y is carbon are prepared as follows:

Spiro[isobenzofuran-1(3H),4'-piperidine] according to the methoddescribed by Marxer et al, J. Org. Chem. 1975, 40, 1427. In acorresponding mannerspiro[isobenzofuran-1(3H),3'-8'-azabicyclo[3',2',1']octane] was preparedfrom N-methyl-8-azabicyclo[3,2,1]octan-3-ones;

2,3-Dihydro-spiro[1H-indene-1,4'-piperidine] and3,4-dihydro-spiro[naphtalene-1-(2H),4'-piperidine] following amodification of the method of J. Med. Chem., 1992, 35(11), 2033-2039 andFrench Patent. No. 1,335,831;

1'-Methyl-spiro[benzo[c]thiophene-1(3H),4'-piperidine] according to themethod described by Parham et al, J. Org. Chem. 1976, 41, 2628. Thecorresponding demethylated derivative was obtained by treatment withethyl chloroformate followed by alkaline hydrolysis of the intermediaryethyl carbamate;

1'-Phenylmethyl-spiro[1H-2-benzopyran-4(3H),4'-piperidine] according tothe method described by Yamamoto et al, J. Med. Chem., 1981, 24, 194.The corresponding debenzylated derivative is obtained by hydrogenationin the presence of a palladium catalyst;

3,4-Dihydro-1'-phenylmethyl-spiro[2H-2-benzopyran-1,4'-piperidine] and3,4-dihydro-1'-phenylmethyl-spiro[1H-1-benzopyran-2,4'-piperidine]according to the method described by Yamamoto et al, Chem. Pharm. Bull.1981, 29, 3494. The corresponding debenzylated derivative is obtained bytreatment with ethyl chloroformate followed by alkaline hydrolysis ofthe intermediary ethyl carbamate;

1'-Phenylmethyl-spiro[2H-1-benzopyran-2,4'-piperidine] is obtainedaccording to the method described by Yamamoto et al, Chem. Pharm. Bull.1981, 29, 3494. The corresponding debenzylated derivative is obtained byhydrogenation in the presence of a palladium catalyst;

1'-Phenylmethyl-spiro[3H-2-benzopyrano3,4'-piperidine]-1(4H)-oneaccording to the method described by Yamamoto et al, J. Med. Chem. 1981,24, 194. Reduction with lithium aluminium hydride followed by treatmentwith phosphoric acid according to the procedure described by Marxer etal, J. Org. Chem. 1975, 40, 1427 yields1,4-dihydro-1'-phenylmethyl-spiro[3H-2-benzopyran-3,4'-piperidine] whichis debenzylated by hydrogenation in the presence of a palladiumcatalyst;

1'-Benzyl-spiro[4H-1-benzopyran-4,4'-piperidine] is obtained by a methodwhich is analogeous to the one described in EP-A1-0 414 289 for thesynthesis of 1'-benzyl-1,4-dihydrospiro[naphthalene-1,4'-piperidine].Hydrogenation in the presence of a Pd catalyst gave2,3-dihydrospiro[4H-1-benzopyran-4,4'-piperidine];

Spiro[1,3-benzodioxole-2,4'-piperidine] is obtained by refluxing1-ethoxycarbonyl-4-piperidinone and catechol in toluen solution in thepresence of p-toluenesulphonic with continous removal of water followedby removal of the benzyl group by hydrogenation in the presence of apalladium catalyst.

The substituents R¹ -R⁶ are introduced by applying suitably substitutedstarting compounds to methods analogously to the above mentioned.

In the following the invention is further illustrated by some exampleswhich, however, may not be construed as limiting.

Melting points are determined on a Buchi SMP-20 apparatus and areuncorrected. ¹ H NMR spectra are recorded at 250 MHz on a Bruker AC 250spectrometer. Deuterand chloroform (99,8% D), deuteriumoxide (99,9% D)or dimethylsulfoxide (99,9% D) were used as solvents. TMS was used asinternal reference standard. Chemical shift values are expressed in ppmvalues. The following abbreviations are used for multiplicity of NMRsignals: s=singlet, d=doublet, t=triplet, q=quartet, p=pentet, dd=doubledoublet, dt=double triplet, tt=triplet of triplets, m=multiplet.

EXAMPLE 1

(method a)

1,4-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]butane 1a.

To a solution of spiro[isobenzofuran-1(3H),4'-piperidine] (3 g) indichloromethane (25 ml) was added triethylamine (3 ml). The mixture wascooled to 5° C. and a solution of succinic acid dichloride (1 g) indichloromethane (10 ml) was added dropwise during 1/2 h. After stirringfor an additional hour at room temperature the mixture was elutedthrough silica gel with dichloromethane. The diamide was retained by thesilica gel and was subsequently extracted from the gel with a mixture ofethyl acetate and THF (1:1). The solvents were evaporated in vacuo andthe remaining solid product was recrystallized from diethyl ether.Yield: 2.8 g. Mp 212° C. To a suspension of LiAlH₄ (3 g) in dry THF (150ml) was added in small portions all of the diamide (2.8 g) preparedabove. The temperature was slowly raised to reflux and kept there for 2hours. After cooling to below 10° C. excess of LiAlH₄ was destroyed bycautious addition of concentrated aqueous NaOH solution (3 ml) and water(15 ml). Inorganic salts were filtered off and the solvents evaporatedin vacuo. The remaining solid product was stirred with diethyl ether andthe crystalline title compound 1a was filtered off and dried. Yield 1.4g. Mp 128° C. ¹ H NMR (CDCl₃) δ1.55-1.65 (m,4H), 1.80 (d,4H), 2.00(dt,4H), 2.45 (t,4H), 2.45-2.55 (m,4H), 2.95 (broad d,4H), 5.05 (s, 4H),7.10-7.30 (m,8H).

In a similar way the following compounds were prepared:

1,4-Bis[4-(4-fluorophenyl)piperidin-1-yl]butane 1b, mp 124° C. ¹ H NMR(CDCl₃) δ1.55-1.60 (m,4H), 1.70-1.85 (m,6H), 2.05 (dt,4H), 2.40 (broadt,4H), 2.45 (tt,2H), 6.95 (t, 4H), 7.20 (dd,4H);

1,4-Bis[1,4-dihydro-spiro[2-benzopyran-3,4'-piperidin]-1'-yl]butane 1c,mp 147°-148° C. ¹ H NMR (CDCl₃) δ1.50-1.60 (m,4H), 1.65 (dt,4H), 1.80(broad d,4H), 2.35-2.45 (m,8H), 2.55-2.65 (m,4H), 2.65 (s,4H), 4.75(s,4H), 6.95-7.20 (m,8H);

1,5-Bis[4-(4-fluorophenyl)piperidin-1-yl]pentane, 2.5 fumarate 1d, mp176° C. ¹ H NMR (DMSO-d₆) δ1.35 (broad p,2H), 1.65 (broad p,4H),1.80-1.90 (m,8H), 2.50-2.70 (m,6H), 2.75 (t,4H), 3.30 (d,4H), 6.55(s,5H), 7.10 (t,4H), 7.25 (dd, 4H);

1,4-Bis[4-(4-fluorophenyl)piperazin-1-yl]butane 1e, mp 156°-158° C. ¹ HNMR (CDCl₃) δ1.60 (broad p,4H), 2.45 (broad t,4H), 2.60 (t,8H), 3.15(t,8H), 6.85-7.00 (m,8H);

1,6-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]hexane 1f, mp99°-102° C. ¹ H NMR (CDCl₃) δ1.35 (broad p,4H), 1.60 (broad p,4H), 1.80(d,4H), 2.00 (dt,4H), 2.35-2.55 (m,8H), 2.85 (broad d,4H), 5.05 (s,4H),7.15-7.30 (m,8H);

1,4-Bis[6-fluoro-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]butane1g, mp 134°-135° C. ¹ H NMR (CDCl₃) δ1.55-1.65 (m,4H), 1.75 (d,4H), 2.00(dt,4H), 2.40 (dt,4H), 2.40-2.50 (m,4H), 2.90 (broad d,4H), 5.05 (s,4H), 6.80 (dd,2H), 6.95 (dt,2H), 7.15 (dd,2H);

1,5-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]pentanetetrafumarate 1h, mp 156°-157° C. ¹ H NMR (DMSO-d₆) δ1.35 (broad p,2H),1.60-1.80 (m,8H), 2.25 (dt,4H), 2.80-2.95 (m,8H), 3.25 (broad d,4H),5.05 (s,4H), 7.20-7.35 (m,8H);

1,4-Bis[spiro[1,3-benzodioxol-2,4'-piperidin]-1'-yl]butane 1i, mp164°-167° C. ¹ H NMR (CDCl₃) δ1.60 (broad p,4H), 2.15 (t,8H), 2.50(t,4H), 2.70 (t,8H),6.85 (s,8H);

1,4-Bis[6-(trifluoromethyl)-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]butane,dihydrochloride 1j, mp 305°-310° C. ¹ H NMR (DMSO-d₆) δ1.70-1.95 (m,8H),2.30-2.50 (m,4H), 3.05-3.60 (m,12H), 5.05 (s,4H), 7.45 (broad s,2H),7.65 (d,2H), 7.75 (d,2H);

1,4-Bis[1,3-dihydro-spiro[2-benzopyran-4,4'-piperidin]-1'-yl]butane 1k,mp 173°-176° C. ¹ H NMR (CDCl₃) δ1.55 (p,4H), 1.75 (d,4H), 2.05-2.20(m,8H), 2.45 (t,4H), 2.90 (d,4H), 3.90 (s,4H), 4.80 (s,4H), 6.95 (d,2H),7.15 (t,2H), 7.25 (t,2H), 7.50 (d,2H);

1,4-Bis[5-methyl-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]butane1l, mp 149°-151° C. ¹ H NMR (CDCl₃) δ1.55 (p,4H), 1.75 (d,4H), 1.95(dt,4H), 2.90 (s, 6H), 2.35-2.50 (m,8H), 2.85 (d,4H), 5.05 (s,4H),6.95-7.10 (m,6H);

1,4-Bis[7-fluoro-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]butane1m, mp 175°-179° C. ¹ H NMR (CDCl₃) δ1.55-1.65 (m,4H), 1.80 (d,4H), 2.00(dt,4H), 2.30-2.50 (m,16H), 2.90 (broad d,4H), 5.05 (s, 4H), 6.90-7.00(m,4H), 7.20-7.25 (m,2H);

1,4-Bis[spiro[isobenzofuran-1(3H),3'-8'-azabicyclo[3',2',1']octan]-8'-yl]butane1n, mp 175°-179° C. ¹ H NMR (CDCl₃) δ1.65 (p,4H), 1.90 (d,4H), 1.95-2.05(m,4H), 2.15 (dd,4H), 2.15-2.30 (m,4H), 2.50 (broad s,4H), 3.30 (broads,4H), 5.05 (s,4H), 7.10-7.30 (m,8H);

1,4-Bis[3-(4-fluorophenyl)-8-azabicyclo[3,2,1]oct-2-en-8-yl]butane 1o,mp 163°-165° C. ¹ H NMR (CDCl₃) δ1.55-1.65 (m,6H), 1.90 (dt,2H),1.95-2.25 (m,6H), 2.55 (broad t,4H), 2.80 (dd,2H), 3.50 (broad t,4H),6.20 (d,2H), 7.00 (t,4H), 7.00 (t,4H), 7.30 (dd,4H);

1,4-Bis[spiro[1-benzopyran-2,4'-piperidin]-1'-yl]butane, difumarate 1p,mp 192°-198° C. ¹ H NMR (DMSO-d₆) δ1.55-1.65 (m,4H), 1.80-2.05 (m,8H),2.60-2.80 (m,8H), 2.80-2.95 (m,4H), 5.75 (d,2H), 6.50 (d,2H), 6.55(s,4H), 6.80-6.90 (m,4H), 7.10-7.20 (m,4H); 7.20 (m,4H);

1,4-Bis[3,4-dihydro-spiro[naphthalene-1(2H),4'-piperidin]-1'-yl]butane1q, mp 167°-175° C. ¹ H NMR (CDCl₃) δ1.55-1.70 (m,8H), 1.70-1.90 (m,8H),2.20 (dt, 4H), 2.20-2.35 (m,4H), 2.45 (broad t,4H), 2.75-2.90 (m,8H),7.00-7.20 (m,6H), 7.55 (d,2H);

1,4-Bis[3,4-dihydro-spiro[1-benzopyran-2,4'-piperidin]-1'-yl]butane,difumarate 1r, mp 202°-204° C. ¹ H NMR (DMSO-d₆) δ1.50-1.60 (m,4H),1.70-1.90 (m,12H), 2.60-2.80 (m,12H), 2.80-2.95 (m,4H), 6.55 (s,4H),6.70-6.90 (m,4H), 7.05-7.20 (m,4H);

1,4-Bis[spiro[isobenzothiophene-1(3H),4'-piperidin]-1'-yl]butane 1s, mp155°-160° C. ¹ H NMR (CDCl₃) δ1.55-1.65 (m,4H), 1.90-2.00 (m,4H),2.15-2.30 (m,8H), 2.45 (broad t,4H),3.00-3.10-2.55 (m,4H), 4.15 (s, 4H),7.25 (s,8H);

1,4-Bis[spiro[1-benzopyran-2,4'-piperidin]-1'-yl]butane, 1.25 fumarate1t, mp 226°-230° C. ¹ H NMR (D₂ O) δ1.90 (broad s,4H), 2.15-2.45 (m,8H),2.90 (t,4H), 3.20-3.65 (m,12H), 3.95 (t,4H), 6.65 (s,2.5H), 7.15-7.40(m,8H);

1,4-Bis[spiro[1-benzopyran-4,4'-piperidin]-1'-yl]butane, 1u, mp163°-165° C. ¹ H NMR (CDCl₃) δ1.50-1.65 (m,8H), 1.95 (t,4H), 2.10-2.25(m,8H), 2.40 (t,4H), 2.75-2.90 (m,4H), 4.10 (t,4H), 6.80 (dd,2H), 6.90(dt, 2H), 7.05 (dt,2H) 7.40 (dd,2H).

EXAMPLE 2

(method b)

1,3-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]propane difumarate2a.

To a solution of spiro[isobenzofuran-1(3H),4'-piperidine] (1.9 g) indichloromethane (40 ml) was added triethylamine (2.3 ml). After coolingto 10° C. a solution of 3-chloropropionic acid chloride (1.7 g) indichloromethane (15 ml) was added dropwise during 10 min. The mixturewas stirred at room temperature for another hour. The1'-(3-chloropropanoyl)-spiro[isobenzofuran-1(3H),4'-piperidine] waspurified by subjecting the reaction mixture to column chromatography onsilica gel (eluted with ethyl acetate/heptane 60:40). Yield 1.8 g as anoil. As a result of elimination of hydrogen chloride1'-(2-propenoyl)-spiro[isobenzofuran-1(3H),4'-piperidine] was isolatedas a by-product. Yield 0.7 g as an oil. Both the 3-chloropropanoic acidamide and the propenoic acid amide were dissolved in methyl isobutylketone (MIBK) (40 ml). To this solution K₂ CO₃ (1.5 g) andspiro[isobenzofuran-1(3H),4'-piperidine] (1.8 g) were added. Theresulting mixture was refluxed overnight. Inorganic salts weresubsequently filtered off and MIBK evaporated in vacuo. The resulting1,3-bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]propanoic acidamide was purified by column chromatography on silica gel (eluted withethyl acetate containing 4% of triethylamine). Yield 2.2 g as a viscousoil. To a suspension of LiAlH₄ (0.8 g) in dry THF was added all of theabove isolated mono-amide (2.2 g) in THF solution (25 ml). The resultingmixture was refluxed for 2 hours. Excess LiAlH₄ was destroyed bycautiously adding concentrated aqueous NaOH (1 ml) at 10° C. followed byaddition of water (5 ml). Inorganic salts were filtered off and THF wasevaporated in vacuo. The remaining oil was dissolved in ethanol (15 ml)and fumaric acid was added (1.1 g). Upon heating to 60° C. the fumaricacid salt of the title compound 2a crystallized. Yield 2.2 g. Mp232°-233 ° C. ¹ H NMR (DMSO-d₆) δ1.70 (d,4H), 1.95 (broad p,2H), 2.10(dt,4H), 2.65 (t,4H), 2.70-2.80 (m,4H), 3.15 (broad d,4H), 5.00 (s, 4H),6.55 (s,4H), 7.20-7.35 (m,8H).

In a similar way the following compounds were prepared:

1,3-Bis[4-(4-fluorophenyl)piperidin-1-yl]propane 2b, mp 59°-61° C. ¹ HNMR (CDCl₃) δ1.75-1.90 (m,10H), 2.05 (dt,4H), 2.45 (t,4H), 2.45-2.55(m,2H), 3.05 (broad d,4H), 6.95 (t, 4H), 7.20 (dd,4H);

1,2-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]ethane 2c, mp152°-153° C. ¹ H NMR (CDCl₃) δ1.80 (d,4H), 2.00 (dt,4H), 2.50 (dt,4H),2.65 (s,4H), 2.90 (broad d,4H), 5.05 (s, 4H), 7.10-7.30 (m,8H);

1,2-Bis[4-(4-fluorophenyl)piperidin-1-yl]ethane 2d, mp 151°-154° C. ¹ HNMR (CDCl₃) δ1.70-1.85 (m,8H), 2.10 (dt,4H), 2.45-2.55 (m,2H), 2.60(s,4H), 3.05 (broad d,4H), 6.95 (t, 4H), 7.15 (dd,4H).

EXAMPLE 3

(method a)

N,N-Bis[2-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-ylethyl]-N-cyclopentylamine, trihydrochloride 3a.

To a solution of spiro[isobenzofuran-1(3H),4'-piperidine] (14 g) indichloromethane (160 ml) triethylamine (11 ml) was added. After coolingto 10° C. a solution of chloroacetylchloride (8 ml) in dichloromethane(10 ml) was added dropwise during 20 minutes. The reaction mixture wasfinally allowed to reach room temperature. The mixture was subsequentlyfiltered through silica gel (eluted with ethyl acetate/n-heptane 60:40)affording 12 g of the α-chloroacetamide derivative. A mixture of thethus obtained α-chloroacetamide derivative (1.4 g) and cyclopentylaminein MIBK (25 ml) was refluxed for 2 h. The solvent was evaporated invacuo and the cyclopentylamino derivative was extracted from an alkaline(pH>9) aqueous solution with ethyl acetate. The organic phase was workedup as above yielding 2.0 g of the α-(cyclopentylamino)acetamidederivative as a visceous oil. To a solution of theα-(cyclopentylamino)acetamide derivative (2 g) in MIBK1'-chloracetylspiro[isobenzofuran-1(3H),4'-piperidine] (1.4 g) andpotassium carbonate (1 g) were added. The mixture was refluxed for 3 h.After cooling to room-temperature the mixture was filtered throughsilica gel (eluted with 4% triethylamine in ethyl acetate. Evaporationof the solvents afforded 2.4 g of the diamide which was reduced withLiAlH₄ as described in example 1. The title compound 3a crystallizedfrom a mixture of ethanol and acetone (1:4). Yield 1.3 g, mp 258°-260°C. ¹ H NMR (DMSO-d₆) δ1.50-2.45 (m,16H), 3.25-3.80 (m,17H), 5.05 (s,4H),7.10-7.40 (m,8H).

In a similar way the following compound was prepared:

N,N-Bis[2-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-ylethyl]-N-methylamine,trihydrochloride 3b. Mp 265°-266° C. ¹ H NMR (DMSO-d₆) δ1.90 (d,4H),2.50-2.90 (m,7H), 3.25 (t,4H), 3.50-3.90 (m,12H), 5.05 (s,4H), 7.15-7.40(m,8H).

EXAMPLE 4

(method a)

1,4-Bis[spiro[ind-2-en-1,4'-piperidin]-1'-yl]butane 4a.

The following method is adapted from a method in J. Med. Chem. 1992, 35(11), 2033-2039. A solution of inden (18 ml) in dry THF (75 ml) wascooled to 0° C. and lithium bis(trimethylsilyl)amide (300 ml solution)was added dropwise during 20 minutes. After stirring for 1/2 h at 0° C.a solution of N-t-butyloxycarbonyl-N,N-bis(2-chloroethyl)amine (36 g) indry THF (100 ml) was added during 1/2 h with ice cooling. After 2 hstirring at 0° C. the solvents were evaporated in vacuo. The remainingoil was subjected to column chromatography (eluted with heptane/diethylether 80:20) affording 19 g of the t-butyloxycarbonyl spiropiperidinederivative as a pure oil. Deprotection of the spiropiperidine wasachieved by adding it (14 g) cautiously to trifluoroacetic acid (75 ml)at room temperature. Excess trifluoroacetic acid was evaporated invacuo. The remaining viscous oil was dissolved in dichloromethane (150ml) and triethyl amine (30 ml) was added. At 0°-5° C. succinic aciddichloride (3.1 g)in dichloromethane (15 ml) was added dropwise. Themixture was finally stirred for an hour at room temperature. Water (500ml) and hydrochloric acid (pH<1) were added. The organic phase wasworked-up leaving the diamide as an oil (11.6 g). A solution of thediamide (11 g) in dry THF (100 ml) was added dropwise to a suspension ofLiAlH₄ (5 g) in dry THF (100 ml) during 1/2 h at 40°-50° C. Afterrefluxing for 2 h the mixture was cooled to 10° C. and conc. aqueousNaOH solution (5 ml) and water (15 ml) were added cautiously. Inorganicsalts were filtered off and the solvents were evaporated in vacuo. Thetitle compound 4a was purified by column chromatography on silica gel(eluted with ethyl acetate/ethanol/triethyl amine 90:10:4) and finallycrystallized from ethyl acetate. Yield 4.3 g. Mp 121°-122 ° C. ¹ H NMR(CDCl₃) δ1.40 (broad d,4H), 1.65 (broad p,4H), 2.25 (dt,4H), 2.35(t,4H), 2.55 (broad t,4H), 3.05 (broad d,4H), 6.75 (d,2H), 6.85 (d,2H),7.15-7.40 (m,8H).

EXAMPLE 5

(method e)

1,4-Bis[spiro[indan-1,4'-piperidin]-1'-yl]butane 5a.

To a solution of 1,4-Bis-spiro[ind-2-en-1,4'-piperidin-1'-yl]butane(compound 4a) (3 g) in ethanol (90 ml) were added acetic acid (5 ml) and5% palladium on carbon (0.9 g). The mixture was hydrogenated in a Parrapparatus for 2 hours ar 3 atm. The catalyst was filtered off and thesolvent evaporated. The remaining oil was dissolved in diluted aqueousNH₄ OH (200 ml, pH>9). The title compound 5a was extracted with ethylacetate and worked-up as above and finally crystallized from ethylacetate. Yield 1.6 g. Mp 113°-115° C. ¹ H NMR (CDCl₃) δ1.55-1.65 (m,8H),1.95-2.10 (m,8H), 2.15 (t,4H), 2.45 (broad s,4H), 2.95 (t,8H), 7.10-7.30(m,8H).

EXAMPLE 6

1,4-Bis[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]butane 6a

To a solution of piperidin-4-ethylene ketal (7 g) (commerciallyavailable) and triethylamine in dichloromethane (50 ml) was addeddropwise succininc acid dichloride (3.1 g) in dichloromethane (25 ml) at10° C. during 15 minutes. After stirring for 1 h at room temperaturewater (200 ml) was added and the organic phase was subsequentlyworked-up. The crude crystalline diamide (7.4 g) melted at 120° C. To asuspension of LiAlH₄ (20 g) in dry THF (400 ml) a solution of thediamide (70 g) in dry THF (700 ml) was added dropwise at 40° C. during45 minutes. After refluxing for 2 h the mixture was cooled to 10° C. andconc. aqueous NaOH solution (10 ml) and water (30 ml) were addedcautiously. Inorganic salts were filtered off and the solvents wereevaporated in vacuo leaving the 1,4-bis-(1-piperidino)butane derivative(62 g) as an oil. The ketone group was deprotected by adding perchlorioacid (240 ml) to a solution of the 1,4-bis(1-piperidino)butanederivative (40 g) in dichloromethane at -10° C. The resulting mixturewas stirred at room temperature for 70 hours. Ice (2 kg) was added andpH was adjusted to >9 by addition of conc. aqueous NaOH solution. Theorganic phase was separated and subsequently worked up yielding the1,4-bis(4-oxopiperidin-1-yl)butane (26 g) as an oil which was usedwithout further purification. A solution of n-butyllithium in hexane(200 ml, 1.6M) was added to dry diethyl ether (200 ml) while cooling.The resulting solution was cooled to -50° C. and a solution of1-bromo-4-fluorobenzene in dry diethyl ether (200 ml) was added during1/2 h at -45° C. After stirring for another 1/2 h a solution of1,4-bis(4-oxopiperidin-1-yl)butane (24 g) in dry diethyl ether was addeddropwise during 40 minutes. The temperature was finally allowed to raiseto 0° C. The mixture was poured onto ice (1.5 kg). To adjust pH<1 dil.hydrochloric acid was cautiously added. The organic phase was separatedand discarded. To the acidic aqueous solution was added NH₄ OH untilpH>9. The 1,4-bis[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]butane (10g) was extracted with ethyl acetate (2×50 ml) and isolated as an oil.Water elimination was accomplished by dissolving the obtainedpiperidin-4-ol derivative (10 g) in trifluoroacetic acid (50 ml) andrefluxing for 1 h. After cooling to room temperature the mixture waspoured onto ice (2 kg) and ethyl acetate (500 ml). Diluted aqueous NH₄OH was added to adjust pH>9 and the organic phase was separated andsubsequently worked-up as above. The title compound 6a crystallized fromethyl acetate. Yield 6.1 g. Mp 165°-167° C. ¹ H NMR (CDCl₃) δ1.65 (broadp,4H), 2.45-2.55 (m,8H), 2.75 (t,4H), 3.15 (q,4H), 6.00 (broad s,2H),7.00 (t,4H), 7.35 (dd,4H).

EXAMPLE 7

(method a)

N,N-Bis[2-[4-(4-fluorophenyl)piperidin-1-yl]ethyl]aniline 7a

To a solution of aniline (49 g) in ethanol (400 ml) sodium acetate (130g) and ethyl bromoacetate (250 g) were added. The mixture was refluxedovernight and was subsequently filtered. The solvents were evaporated invacuo and the remaining oil was distilled at reduced pressure (12 mmHg).Unreacted ethyl bromoacetate and the mono alkylated aniline were thusdistilled off leaving the crude diethyl N,N-anilinodiacetate (31 g)which was used without further purification. To a solution of thisdiester (31 g) in ethanol (200 ml) were added KOH (20 g) and water (30ml). Hydrolysis was accomplished by refluxing for 2 h. Ethanol and waterwere evaporated in vacuo and the remaining di-potassium salt wasdissolved in water (500 ml). Concentrated hydrochloric acid was added toadjust pH<1. The N,N-bis(carboxymethyl)aniline was extracted with ethylacetate (2×100 ml). The crude product (24 g) resulting after work-up ofthe organic phase was used without further purification. A mixture ofthe crude N,N-bis(carboxymethyl)aniline (3.4 g),4-(4-fluorophenyl)piperidine (6 g), dicyclohexylcarbodiimide (8.5 g),p-toluenesulphonic acid (150 mg) in anh. pyridine (50 ml) was stirredovernight at 25°-30° C. Water (500 ml) and ethyl acetate (300 ml) wereadded and concentrated hydrochloric acid was cautiously added untilpH=3. The organic phase was worked-up as above. The crude diamide waspurified by column chromatography on silica gel (eluted with ethylacetate). Yield 4.2 g, mp 167°-168° C. Reduction of the diamide (4.2 g)with LiAlH₄ according to the method described in Example 1 afforded thetitle compound 7a. Yield 0.9 g. Mp 104°-105° C. (crystallized fromdiethyl ether). ¹ H NMR (CDCl₃) δ1.75-2.00 (m,8H), 2.20 (dt,4H), 2.60(t,4H), 2.45-2.55 (m,2H), 3.15 (broad d,4H), 3.55 (t,4H), 6.70-6.80(m,3H), 7.05 (t, 4H), 7.20-7.30 (m,6H).

In a corresponding way the following compound was prepared from3-(4-fluorophenyl)glutaric acid dichloride andspiro[isobenzofuran-1(3H), 4'-piperidine]:

1,5-Bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]-3-(4-fluorophenyl)pentane,difumarate 7b, mp 175°-177° C. ¹ H NMR (DMSO-d₆) δ1.70 (d,4H), 1.80-2.20(m,8H), 2.40-2.50 (m,1H), 2.60-2.80 (m,8H), 3.10 (broad s,4H), 5.00 (s,4H), 6.55 (s, 4H), 7.05-7.35 (m,12H).

EXAMPLE 8

(method a)

Bis[2-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-ylethyl]sulphide,difumarate 8a

To a solution of spiro[isobenzofuran-1(3H),4'-piperidine] (14 g) andtriethylamine (12 ml) in dichloromethane (140 ml) cooled to 10° C. asolution of bromoacetyl bromide (7 ml) in dichloromethane (25 ml) wasadded dropwise during 15 minutes. The mixture was further stirred atroom temperature for 45 minutes. The crude reaction mixture was directlypoured onto silica gel and the bromoacetamide ofspiro[isobenzofuran-1(3H),4'-piperidine] was eluted with ethylacetate/heptane 3:2. Yield 5.6 g. To ethyl thioglycolate (2.4 g) inethanol (40 ml) was added solid potassium t-butoxide (2.3 g) in smallportions. To the resulting potassium ethyl thioglycolate was added thebromoacetamide (3.8 g) from above. The mixture was stirred overnight andthe1'-ethoxycarbonylmethylthiomethylcarbonyl-spiro[isobenzofuran-1(3H),4'-piperidine](3.8 g) was worked up by extraction with diethyl ether from water. Theethyl ester (3.8 g) was hydrolyzed to the corresponding1'-carboxymethylthiomethylcarbonyl-spiro[isobenzofuran-1(3H),4'-piperidine] (3.2 g) by refluxing with KOHin aqueous ethanol according to the procedure in Example 7. Thecarboxylic acid (3.1 g) was refluxed with thionylchloride (1.5 ml) and adrop of DMF in dichloromethane (50 ml) for 1 h. Excess ofthionylchloride was carefully evaporated twice with n-heptane in vacuo.To a cooled (10° C.) solution ofspiro[isobenzofuran-1(3H),4'-piperidine] (2 g) and triethylamine (2.5ml) in dichloromethane (40 ml) was added dropwise a solution of theabove obtained crude carboxylic acid chloride (3 g) in dichloromethane(25 ml). After stirring for another hour at room temperature the diamide(2.9 g) was isolated by subjecting the crude reaction mixture to columnchromatography on silica gel (eluted with ethyl acetate). The totalamount of diamide was reduced with LiAlH₄ according to the methoddescribed in Example 1. Yield 2.2 g. The difumarate salt of the titlecompound 8a crystallized from ethanol/acetone 1:1. Mp 92°-94° C. ¹ H NMR(DMSO-d₆) δ1.65 (d,4H), 2.05 (dt,4H), 2.65 (t,4H), 2.85 (s,8H), 3.05(d,4H), 5.00 (s,4H), 6.60 (s,4H), 7.20-7.35 (m,8H).

EXAMPLE 9

Bis[2-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-ylethyl]sulphone 9a

Bis[2-spiro[isobenzofuran-1(3H),4'-piperidin-1'-yl]ethyl]sulphide (0.8g) from Example 8 was dissolved in trifluoroacetic acid (10 ml) andcooled to 0° C. A cold solution of 35% H₂ O₂ (1 ml) in trifluoroaceticacid (4 ml) was added dropwise during 5 minutes. After heating for 1 hat 50° C. the reaction mixture was poured into ethyl acetate (200 ml)and diluted aqueous NH₄ OH (500 ml) (cooled with ice). The organic phasewas separated and worked up as above. The crude product was purified bycolumn chromatography on silica gel (eluted with ethylacetate/triethylamine 100:4). The title compound 9a crystallized bystirring with diethyl ether. Yield 0.6 g. Mp 170°-172° C. ¹ H NMR(CDCl₃) δ1.80 (d,4H), 1.95 (dt,4H), 2.55 (dt,4H), 2.85 (broad d,4H),3.00 (t,4H), 3.35 (t,4H), 5.05 (s, 4H), 7.10-7.30 (m,8H).

EXAMPLE 10

(method b)

Bis[2-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-ylethyl]ether,dihydrochloride 10a

To spiro[isobenzofuran-1(3H),4'-piperidine] (15 g) in ethanol (150 ml)was added finely powdered potassium carbonate. Ethyl bromoacetate (10ml) was added dropwise at 25°-30° C. The mixture was finally stirred at50°-55° C. for 1 h. Inorganic salts were filtered off and the ethanolevaporated in vacuo. The crude1'-ethoxycarbonylmethyl-spiro[isobenzofuran-1(3H),4'-piperidine] wasextracted from water with diethyl ether and worked-up as above. Yield 20g as an oil. The ethyl ester (20 g) was reduced with LiAlH₄ according tothe method in Example 1 yielding the1'-(2-hydroxyethyl)-spiro[isobenzofuran-1(3H),4'-piperidine] (12 g) asan oil. To a suspension of NaH (1.4 g 50% in oil) in dry THF (40 ml) wasadded dropwise at room temperature a solution of1'-(2-hydroxyethyl)-spiro[isobenzofuran-1(3H),4'-piperidine] (6 g) indry THF (25 ml). Hydrogen gas evolves. After stirring for another 20minutes a solution of1'-chloroacetyl-spiro[isobenzofuran-1(3H),4'-piperidine] (4 g) (preparedas the corresponding bromoacetyl derivative in Example 8) in dry THF wasadded dropwise at 25°-30° C. After stirring for another 1.5 h the2-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-ylethylspiro[isobenzofuran-1(3H),4'-piperidin]-1'-ylcarbonylmethyl ether (6 g)was isolated by extraction with ethyl acetate from water and finallypurified by column chromatography on silica gel (eluted with ethylacetate/ethanol/triethylamine 80:20:4). The thus isolated mono-amide(4.5 g) was reduced with LiAlH₄ according to the method in Example 2affording the title compound 10a. The dihydrochloride salt crystallizedfrom acetone. Yield 2.2 g. Mp 141°-143° C. ¹ H NMR (DMSO-d₆) δ1.85(d,4H), 2.50-2.75 (m,4H), 3.10-3.70 (m,12H), 3.85 (broad s,4H), 5.05(s,4H), 7.15-7.40 (m,8H), 10.60 (broad s,2H).

EXAMPLE 11

(method c)

1,6-Bis[5-methyl-spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]hexane11a

A solution of 5-methyl-spiro[isobenzofuran-1(3H),4'-piperidine] (4 g),1,6-dibromohexane (2.2 g), finely powdered potassium carbonate (2.7 g)and a crystal of potassium iodide in MIBK (150 ml) was refluxed for 4 h.Inorganic salts were filtered off and MIBK evaporated. Columnchromatography on silica gel (eluted with ethylacetate/ethanol/triethylamine 75:25:4) gave the pure title compound 11a.Yield 1.0 g. Mp 113°-116° C. (recrystallized from 2-propyl ether). ¹ HNMR (CDCl₃) δ1.30-1.45 (m,4H), 1.50-1.65 (m,4H), 1.80 (d,4H), 2.00(dt,4H), 2.35 (s,6H), 2.45-2.50 (m,8H), 2.85 (broad d,4H), 5.05 (s, 4H),6.95-7.10 (m,6H).

EXAMPLE 12

(method c)

1,3-Bis[4-(4-fluorophenyl)piperidin-1-yl]-2-propanol 12a

A mixture of 4-(4-fluorophenyl)piperidine (2.6 g), epichlorhydrine (1.1ml), potassium carbonate (2.0 g) in MIBK was stirred overnight at roomtemperature. Inorganic salts were filtered off and the solution wassubsequently refluxed for 3 hours. After addition of triethylamine (1ml) the crude reaction mixture was directly subjected to columnchromatography on silica gel (eluted with ethyl acetate/triethylamine100:4). The title compound 12a crystallized from 2-propyl ether. Yield1.2 g. Mp 79°-80° C. ¹ H NMR (CDCl₃) δ1.65-1.90 (m,8H), 2.15 (dt,2H),2.35 (dt,2H), 2.40 (d,4H), 2.45-2.60 (m,2H), 3.10 (t, 4H), 3.95 (p,1H),6.95 (t,4H), 7.15 (dd,4H).

EXAMPLE 13

(method c)

1,3-Bis[4-(4-fluorophenyl)piperazin-1-yl]-2-propanone 13a

To a solution of 1-(4-fluorophenyl)piperazine (12 g) in acetone (40 ml)kept at reflux temperature a solution of 1,3-dichloroacetone (1.3 g) inacetone (10 ml) was added dropwise. The mixture was refluxed for another2 hours. Acetone was evaporated in vacuo. The remaining viscous oil wassubjected to column chromatography on silica gel (eluted with ethylacetate/ethanol/triethylamine 80:20:4). The title compound 13acrystallized from diethyl ether. Yield 0.6 g. Mp 106°-107° C. ¹ H NMR(CDCl₃) δ2.70 (t,8H), 3.15 (t,8H), 3.45 (s, 4H), 6.85-7.00 (m,8H).

PHARMACOLOGY

The compounds of the invention were tested by well recognized andreliable test methods as follows.

Inhibition of ³ H-DTG Binding to Sigma Receptors in Rat Brain in vitro.

By this method the inhibition by drugs of the binding of 2 nM ³ H-DTG(1,3-di-o-tolyl guanidine) to sigma receptors in homogenates ormembranes from rat brain without cerebellum is determined in vitro asmodified from Weber et al. Proc. Natl. Acad. Sci. 1986, 83, 8784.

Tissue preparations:

Homogenate: Rats (150-250 g) are decapitated and the brains (withoutcerebellum) quickly removed and placed on ice, weighed and homogenizedin 100 vol ice-cold (0° C.) 50 mM Tris-buffer (pH 7.7) in an ethanolrinsed glass/teflon homogenizer at 0° C. and kept on ice until use.

P2-membranes: Brains are homogenized in 10 vol 0.32M sucrose in anethanol rinsed glass/teflon homogenizer with 10 strokes up and down. Thehomogenate is centrifuged for 10 min at 900× g_(m) at 4° C. Thesupernatant are decanted and centrifuged for 20 min at 50,000 g_(m) at4° C. The resulting pellet is resuspended in 10 vol ice-cold 50 nMTris-buffer (pH 7.7) and incubated for 30 min. at 37° C. The membranesuspension is then centrifuged for further 20 min. at 50,000 g_(m) at 4°C. The pellet is resuspended in 50 vol. of ice-cold Tris-buffer and usedimmediately.

Binding analysis:

0.5 ml 50 mM Tris-buffer (pH 7.7), 0.25 ml displacer (6×100 μM DTG, 6×[test compound], or Tris-buffer), and 0.25 ml 6×2 nM ³ H-DTG are mixedinto 5 ml plastic test tubes and kept at 4° C. until use. The bindingreaction are initiated by mixing 0.5 ml tissue suspension into thissolution and incubate at 25° C. for 20 min. Glass fiber filters (WhatmanGF/B) are placed on the filter machine which is then closed tight. Justbefore filtration vacuum is turned on, and the filters washed with 0.1%PEI solution from a spray bottle followed by one wash with Tris-buffer.

The binding reaction is stopped by filtration of the assay mixture atreduced pressure (750 mbar) followed by further 3 washes with 5 mlice-cold Tris-buffer. The filters are placed in counting vials and 4 mlscintillation solution added. The vials are counted in a Beckmannscintillation counter.

Buffers and solutions:

50 mM Tris-buffer pH 7.7:7.38 g Trizma-7.7 plus distilled H₂ O up to 1liter. 100 ml 10% polyethylenimin (PEI): 100 ml dest. H₂ O is added toapprox. 20 g 50% PEI which is solubilized by stirring and heating.Diluted (1+99) before use. 6×2 nM ³ H-DTG: The exact volume depends onthe actual concentration of the batch, but is made as close as possibleto 12 nM. The containers for the radioactive solution is rinsed in 96%ethanol before use.

6×100 μM DTG: 14.36 mg/100 ml is kept frozen in 10 ml aliqouts.

³ H-DTG was obtained from NEN Research Products, Du Pont Denmark.Specific activity 62.3 Ci/mmol.

The known sigma receptor ligands BMY 14802 and rimcazole were includedin the test for comparizon purposes.

                  TABLE I    ______________________________________    .sup.3 H DTG BINDING DATA    Compound No.    IC.sub.50 (nM)    ______________________________________    1a              0.64    1b              0.41    1c              16    1d              1.4    1e              0.89    1f              0.71    1g              0.44    1h              2.0    1i              45    1j              19    1k              8.7    1l              23    1m              5.1    1n              99    1o              74    1p              32    1q              4.0    1r              130    1s              0.04    1t              0.38    1u              0.17    2a              0.76    2b              0.17    2c              0.23    2d              0.50    3a              1.5    3b              4.9    4a              4.0    5a              3.1    6a              0.31    7a              3.6    7b              0.72    8a              0.78    9a              1800    10a             2.5    11a             9.7    12a             2.4    13a             2500    BMY 14802       230    Rimcazo1e       180    ______________________________________

It is seen from Table I that the compounds used in the present inventionare very potent sigma receptor ligands as compared to the referencecompounds which are known in the art to be sigma receptor ligands. Asseen many of the compounds tested showed ED₅₀ values in the area below 1nM.

Furthermore, the ability of the present compounds in inhibiting thebinding of ³ H-Prazosin to α₁ adrenoceptors in membranes from rat brainwere determined in vitro according to Hyttel, J et al, J. Neurochem,1985, 44, 1615; Skarsfeldt, T. et al, Eur. J. Pharmacol. 1986, 125, 323.Additionally some of the compounds of the invention were tested withrespect to dopamine D₂ receptor binding activity according to van derWelde et al, Eur. J. Pharmacol. 1987, 134, 211, with respect toserotonin 5-HT_(1A) receptor binding activity according to Hyttel et al.Drug Dev. Res., 1988. 15, 389-404, and with respect to serotonin 5-HT₂receptor binding activity according to Hyttel, Pharmacology &Toxicology, 1987, 61, 126-129.

For most compounds, the affinities for α₁ adrenoceptors and D₂,5-HT_(1A), and 5-HT₂ receptors were very inferior as compared to thepotent binding to sigma receptors. Thus many of the compounds are veryselective sigma receptor ligands. For example with respect to the α₁adrenoceptors and dopamine D₂, serotonin 5-HT_(1A) and 5-HT₂ receptors,ratios of binding IC₅₀ values (alpha/sigma, dopamine/sigma, 5-HT_(1A)/sigma, and 5-HT₂ /sigma, respectively) of 100->1000 have been found.

FORMULATION EXAMPLES

The pharmaceutical formulations of the invention may be prepared byconventional methods in the art. For example: Tablets may be prepared bymixing the active ingredient with ordinary adjuvants and/or diluents andsubsequently compressing the mixture in a conventional tablettingmaschine. Examples of adjuvants or diluents comprise: corn starch,lactose, talcum, magnesium stearate, gelatine, lactose, gums, etc. Otheradjuvants or additives usually used for such purposes such ascolourings, flavourings, preservatives etc. may be used provided thatthey are compatible with the active ingredients. Solutions forinjections may be prepared by dissolving the active ingredient andpossible additives in a part of the vehicle, preferably sterile water,adjusting the solution to desired volume, sterilization of the solutionand filling in suitable ampules or vials. Any suitable additiveconventionally used in the art may be added, e.g. tonicity agents,preservatives, antioxidants, etc.

Typical examples of recipes for the formulation of the invention are asfollows:

    ______________________________________    1) Tablets containing 5.0 mg of Compound 1b calculated as the    free base:    Comp. 1b                 5.0 mg    Lactose                  60 mg    Maize Starch             30 mg    Hydroxypropylcellulose   2.4 mg    Microcrystalline Cellulose                             19.2 mg    Croscarmellose Sodium Type A                             2.4 mg    Magnesium Stearate       0.84 mg    2) Tablets containing 1.0 mg of Compound 1e calculated as the    free base:    Comp. 1e                 1.0 mg    Lactose                  23.5 mg    Maize Starch             46.9 mg    Povidone                 1.8 mg    Microcrystalline Cellulose                             14.4 mg    Croscarmellose Sodium Type A                             1.8 mg    Magnesium stearate       0.63 mg    3) Syrup containing per milliliter:    Comp. 1s                 2.5 mg    Sorbitol                 500 mg    Hydroxyethylcellulose    15 mg    Glycerol                 50 mg    Methyl-paraben           1 mg    Propyl-paraben           0.1 mg    Ethanol                  0.005 ml    Flavour                  0.05 mg    Saccharin Natrium        0.5 mg    Water                    ad 1 ml    4) Solution for injection containing per milliliter:    Comp. 2b                 0.5 mg    Sorbitol                 5.1 mg    Acetic acid, Glacial     0.08 mg    Water for injection      ad 1 ml    ______________________________________

We claim:
 1. A dimeric spirocyclic piperidine compound having theFormula I: ##STR6## wherein n is 1-5;R¹ to R⁴ are independently selectedfrom hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkyl- or di-(C₁₋₆ alkyl)amino,cyano, trifluoromethyl, nitro, trifluoromethylthio ortrifluoromethylsulfonyloxy; R⁵ and R⁶ are independently hydrogen, orC₁₋₆ alkyl; X is O, S, SO, SO₂, or (CH₂)_(m), m being 0 or 1, or X isNR⁷, R⁷ being H, C₁₋₆ alkyl, cycloalkyl, cycloalkylalkyl, phenyl, orphenylalkyl, or X is CR⁸ R⁹, wherein R⁸ and R⁹ are independentlyselected from the group consisting of hydroxy and the substituentsdefined under R⁷, any phenyl group being optionally substituted with oneor more substituents selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,hydroxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkyl or di(C₁₋₆alkyl)amino, cyano, trifluoromethyl or trifluoromethylthio; andZ¹ is O,S, (CH₂)_(q), q being 1,2 or 3, or Z¹ is CH₂ O, CH₂ S, CH₂ CH₂ O, CH₂CH₂ S, CH═CH, CH═CHCH₂, CH₂ OCH₂ CH₂ SCH₂, CH═CH--O, or CH═CH--S; and Z²is O, S or (CH₂)_(p), p being 0 or 1, with the proviso that Z¹ may notbe O, S or (CH₂)_(q), wherein q is 1 when Z² is (CH₂)_(p) wherein p is0;or an acid addition salt thereof.
 2. A pharmaceutical compositioncomprising at least one dimeric piperidine, compound according to claim1 or a pharmaceutically acceptable acid addition salt thereof incombination with one or more pharmaceutically acceptable carriers ordiluents.
 3. A method for treating anxiety or convulsions comprisingadministering a therapeutically effective amount of a compound accordingto claim 1 or a pharmaceutically acceptable acid addition salt thereofto a patient in need thereof.
 4. A compound according to claim 1,wherein n is 1, 2 or
 3. 5. A compound according to claim 1, wherein X is(CH₂)_(m), m being 0 or 1, X is NR⁷, R⁷ being C₁₋₆ alkyl, cycloalkyl,phenyl, or phenyl substituted with halogen or X is S, O or CR⁸ R⁹,wherein R⁸ is hydroxy, phenyl and or phenyl substituted with halogen andR⁹ is hydrogen.
 6. A compound according to claim 1, wherein R² -R⁴ areindependently selected from hydrogen, halogen, C₁₋₆ alkyl andtrifluoromethyl, and R⁵ and R⁶ are hydrogen.
 7. A compound according toclaim 1, wherein Z¹ is (CH₂)_(q), q being 1, 2 or 3, or Z¹ is CH₂ O,(CH₂)₂ O, CH═CH, O, S or CH₂ S; and Z² is O or (CH₂)_(p) wherein p is 0or
 1. 8. A compound according to claim 7, wherein Z² is (CH₂)_(p), pbeing 0, and Z¹ is CH₂ O, CH₂ S or (CH₂)₂ O.
 9. The compositionaccording to claim 2 in unit dosage form containing said compound in anamount of 0.01 to 50 mg.